POS0291 IDENTIFICATION OF SUBSETS OF SLE PATIENTS RESPONSIVE TO IBERDOMIDE BY TRANSCRIPTOMIC ANALYSIS OF BASELINE SAMPLES
Authors: P. Bachali, Y. Hu, N. Delev, P. Schafer, P. Lipsky
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Iberdomide is a high affinity cereblon ligand that promotes ubiquitylation and proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors and, thereby altering specific aspects of immune responsiveness. Iberdomide has been shown to be efficacious in a randomized controlled trial in patients with generalized SLE (NCT03161483) and to be specifically effective in patients with high baseline expression of the interferon gene signature (IGS)<sup>[1,2]</sup>. <h3>Objectives</h3> The goal of this study was to identify subsets of SLE patients responsive to iberdomide more effectively by analyzing baseline gene expression profiles. <h3>Methods</h3> Baseline whole blood samples from 276 female SLE patients from the phase 2b iberdomide trial were utilized for this analysis. These patients had a &gt;/= 6 month history of SLE and disease activity determined by SLEDAI-2K &gt;/=6. Patients were randomized to placebo, or one of three doses of iberdomide (0.15, 0.3 or 0.45 mg per day). Clinical response was determined by the SLE Responder Index 4 (SRI-4) at 24 weeks. RNAseq was performed and analyzed by Gene Set Variation Analysis (GSVA) using 32 informative gene modules and K-means clustering. <h3>Results</h3> Whole blood K-means clustering of the GSVA scores yielded 5 clusters or endotypes (Figure 1). Cluster 0 had the fewest molecular abnormalities, whereas Cluster 1 had the most disturbances in immune function, including enrichments in the interferon gene signature (IGS), immunoproteasome, IL-1/ inflammasome pathway, and neutrophil/granulocyte genes. Clusters 2-3 had intermediate degrees of abnormal enrichment in specific gene modules. Cluster 4 had high IGS, immunoproteasome, plasma cells/Ig chains, and IL-23 complex genes. No differences were noted between the subsets with regard to steroid or hydroxychloroquine use and differed only slightly in disease activity as measured by SLEDAI-2K. In general, cluster 1 had the most severe clinical laboratory measures with the highest anti-dsDNA antibodies and lowest C3 and C4. Clinical responses to iberdomide were confined to clusters 1 and 4. Effect sizes of responses in these groups approximated 30%. Other clusters had higher placebo responses and no additional response to iberdomide. <h3>Conclusion</h3> K-means clustering of GSVA scores from baseline samples of the iberdomide trial successfully clustered patients into endotypes that exhibited differences in response to iberdomide treatment, with the greatest responses observed in patients with the highest IGS, immunoproteasome, plasma cell, inflammasome, and IL-23 pathways. Gene expression based subsetting (endotyping) may be useful to enrich trials for responsive patients. <h3>References</h3> [1]Merrill JT et al. N Engl J Med 2022; 386:1034 [2]Lipsky, PE et al Ann Rheum Dis 2022-222212 <h3>Acknowledgements</h3> Research supported by BMS. <h3>Disclosure of Interests</h3> Prathyusha Bachali: None declared, Yanhua Hu Shareholder of: BMS, Employee of: BMS, Nikolay Delev Shareholder of: BMS, Employee of: BMS, Peter Schafer Shareholder of: BMS, Employee of: BMS, Peter Lipsky: None declared.